Transcriptional repression of the transforming growth factor-beta type I receptor gene by DNA methylation results in the development of TGF-beta resistance in human gastric cancer
- PMID: 10602482
- DOI: 10.1038/sj.onc.1203146
Transcriptional repression of the transforming growth factor-beta type I receptor gene by DNA methylation results in the development of TGF-beta resistance in human gastric cancer
Abstract
The transforming growth factor-beta (TGF-beta) signaling pathway subserves an essential tumor suppressor function in various cell types. A heteromeric complex composed of TGF-beta type I (RI) and type II (RII) receptors is required for TGF-beta signaling. We have identified a subset of human gastric cancer cell lines which are insensitive to TGF-beta and which express a low level of TGF-beta type I receptor mRNA relative to a gastric cancer cell line which is highly responsive to TGF-beta. Using these cells, we show that hypermethylation of a CpG island in the 5' region of the TGF-beta RI gene provides another potentially important mechanism of escape from negative growth control by TGF-beta. This hypermethylation was found in four of five human gastric cancer cell lines and five out of 40 (12.5%) primary tumors examined. In human gastric cancer cell lines, treatment with the demethylating agent, 5-aza-2'-deoxycytidine, resulted in increased expression of the TGF-beta RI gene, but not the RII gene. Transient transfection of an RI expression vector into the TGF-beta resistant SNU-601 cell line restores TGF-beta responsiveness. These findings suggest that one of the mechanisms of escape from autocrine or paracrine growth control by TGF-beta during carcinogenesis could involve aberrant methylation of CpG islands in the 5' region of the TGF-beta RI gene.
Similar articles
-
Sequence-specific enhancer binding protein is responsible for the differential expression of ERT/ESX/ELF-3/ESE-1/jen gene in human gastric cancer cell lines: Implication for the loss of TGF-beta type II receptor expression.Oncogene. 2001 Mar 8;20(10):1235-45. doi: 10.1038/sj.onc.1204227. Oncogene. 2001. PMID: 11313868
-
Truncation of the TGF-beta type II receptor gene results in insensitivity to TGF-beta in human gastric cancer cells.Oncogene. 1999 Apr 1;18(13):2213-9. doi: 10.1038/sj.onc.1202535. Oncogene. 1999. PMID: 10327067
-
Expression of transforming growth factor beta type II receptor reduces tumorigenicity in human gastric cancer cells.Cancer Res. 1997 Jul 15;57(14):2856-9. Cancer Res. 1997. PMID: 9230189
-
The role for transforming growth factor-beta (TGF-beta) in human cancer.Crit Rev Oncog. 1999;10(4):303-60. Crit Rev Oncog. 1999. PMID: 10654929 Review.
-
Transforming growth factor-beta and cancer: a love-hate relationship?Oncol Res. 1997;9(9):447-57. Oncol Res. 1997. PMID: 9495450 Review.
Cited by
-
TGF-β - an excellent servant but a bad master.J Transl Med. 2012 Sep 3;10:183. doi: 10.1186/1479-5876-10-183. J Transl Med. 2012. PMID: 22943793 Free PMC article. Review.
-
Transforming growth factor beta (TGF-beta) and inflammation in cancer.Cytokine Growth Factor Rev. 2010 Feb;21(1):49-59. doi: 10.1016/j.cytogfr.2009.11.008. Epub 2009 Dec 16. Cytokine Growth Factor Rev. 2010. PMID: 20018551 Free PMC article. Review.
-
TGF-beta biology in mammary development and breast cancer.Cold Spring Harb Perspect Biol. 2011 Jan 1;3(1):a003277. doi: 10.1101/cshperspect.a003277. Cold Spring Harb Perspect Biol. 2011. PMID: 20810549 Free PMC article. Review.
-
Expression and mutational analysis of TGF-beta/Smads signaling in human cervical cancers.J Gynecol Oncol. 2009 Jun;20(2):117-21. doi: 10.3802/jgo.2009.20.2.117. Epub 2009 Jun 29. J Gynecol Oncol. 2009. PMID: 19590724 Free PMC article.
-
DNA methylation: old dog, new tricks?Nat Struct Mol Biol. 2014 Nov;21(11):949-54. doi: 10.1038/nsmb.2910. Nat Struct Mol Biol. 2014. PMID: 25372310
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
